Identification of any publication in this section or any section of this application is not an admission that such publication is prior art to the present invention.
As described in Published U.S. Patent Application No. 2004-0209878 A1, filed on Feb. 11, 2004 (the '878 publication), which is incorporated herein in its entirety, 3-alkyl-5-piperidin-1-yl-3,3a-dihydro-pyrazolo[1,5-a]pyrimidin-7-yl)-amino derivatives (as illustrated in Formula I, where R1 is a linear, branched, or cyclic alkyloxy functional group of the structure (—R2a—OH), R2a is a linear, branched or cyclic alkyl group, R2 is a linear, branched or cyclic alkyl group, and R3 is selected from alkylheterocycles, for example, 3-alkylene-pyridine-N-oxide, have activity as cyclin-dependent kinase inhibitor (CDK inhibitor) compounds.

As described in the '878 publication, in these compounds can be prepared through the general routes described below in Scheme I.
Where R1, R2, and R3 are as defined above, R4 and R7 are selected from H and R2, and R5 and R6 are taken together to form an alkyl heterocycle, for example, pyrimidin-1-yl, optionally substituted on any carbon with a linear, branched, or cyclic alkyl, which is optionally substituted with hydroxide. Accordingly, a dicarboxylic acid diester (compound 11, a malonate diester or an appropriately substituted malonate diester derivative where R4 is other than hydrogen) is condensed with pyrazole compound (7) by refluxing in acetic acid, forming a pyridone compound (13). The pyridone compound is subsequently derivatized by dehalogenation it, for example, by treatment with the chlorinating reagent POCl3 to provide the dichloride derivative. The dihalogen derivative (14) is then sequentially treated with amines to provide the amino-functionalized CDK inhibitor product 16, wherein R5 and R6 are taken together to form an alkyl heterocycle, for example, pyrimidin-1-yl, and wherein “R” (Scheme 1) is a linear, branched, or cyclic alkyl, optionally substituted with pyridine N-oxide.
One example of these inhibitors is the compound of Formula II.
The synthesis of the compound of Formula II is described in the '878 publication according to Scheme II:Scheme II:
Step 1—Amidization to Form Substituted Pyrazole

Step 2—Formation and Dehalogenation of pyrazolo[1,5a]pyrimidine

Step 3—Amination (Two Separate, Sequential Reactions)

As described in the '878 publication, Synthetic Scheme II leading to the compound of Formula II has several disadvantages from the standpoint of commercial scale synthesis. In step 1, the starting material (compound “C”) used in the formation of compound “D” is a sticky, viscous oil which is difficult to process (weigh, transfer, and blend). Moreover, step 1, as described in the '878 publication, requires isolation and chromatographic purification of compounds C and D prior to carrying out each subsequent derivatization reaction. In addition, as described in the '878 publication, the reaction of compound C with malonate diester is carried out using the diester as a solvent. After isolation and purification of the resultant malonate adduct, compound D, ring closure to form diketone compound E is carried out in methanol. In accordance with the procedure described in the '878 publication, compound E is isolated and dried, then converted to the corresponding dichloride in N,N-dimethyl aniline by treatment with phosphorous oxychloride (POCl3). The dichloride thus formed was isolated and purified by chromatography prior to the sequential amination reactions. Additionally, the compounds of Formula G and of Formula II require chromatography purification and isolations, as described in the '878 publication.
As further described in the '878 publication, each of the amination reactions were run separately with isolation and chromatographic purification between amination reactions. Accordingly, the '878 publication describes the preparation of the compound of Formula II utilizing a scheme consisting of five separate reaction steps with intervening isolation and purification of the products, each sequential step being carried out in a different solvent system. The overall yield of the compound of Formula II reported for this synthesis, based on starting compound C (Scheme II) is about 20%.